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Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor.


ABSTRACT: A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)(exp). It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)(exp) interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. Ligand 3 binds r(CUG)12 with a low micromolar affinity (K(d) = 8 ± 2 ?M) and disrupts the MBNL1-r(CUG)12 interaction in vitro (K(i) = 8 ± 2 ?M). In addition, ligand 3 is cell and nucleus permeable, exhibits negligible toxicity to mammalian cells, dissolves MBNL1-r(CUG)(exp) ribonuclear foci, and restores misregulated splicing of IR and cTNT in a DM1 cell culture model. Importantly, suppression of r(CUG)(exp) RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1.

SUBMITTER: Wong CH 

PROVIDER: S-EPMC4015652 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor.

Wong Chun-Ho CH   Nguyen Lien L   Peh Jessie J   Luu Long M LM   Sanchez Jeannette S JS   Richardson Stacie L SL   Tuccinardi Tiziano T   Tsoi Ho H   Chan Wood Yee WY   Chan H Y Edwin HY   Baranger Anne M AM   Hergenrother Paul J PJ   Zimmerman Steven C SC  

Journal of the American Chemical Society 20140422 17


A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)(exp). It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)(exp) interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connecte  ...[more]

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